New Avian influenza vaccines emerging

Outbreaks of Avian influenza are economically harmful and also pose a threat to public health. It’s therefore important that effective vaccines are developed so that we can respond promptly to new outbreaks. Jeroen Kortekaas and Riks Maas, both from Wageningen Bioveterinary Research, tell about the new vaccine technologies they’re currently working on.

The eventual Holy Grail is to be a universal vaccine that works against all influenza viruses

Jeroen Kortekaas, virologist

“The eventual Holy Grail is to be a universal vaccine that works against all influenza viruses,” says Jeroen Kortekaas, virologist at Wageningen Bioveterinary Research, who is working with colleagues on new vaccine technologies. Every so often, an infection will crop up at a poultry farm and send shockwaves through the poultry sector. Usually it will be a low pathogenic avian influenza introduced by wild birds. “The highly pathogenic viruses, which cause serious illness, are always the H5 or H7 sub-types,” says Riks Maas, head of the virology department at Wageningen Bioveterinary Research. “But the low pathogenic variants of these sub-types are also cause for concern because they can mutate into a highly pathogenic variant.”

According to Maas, no country in the world has avian influenza better under control than the Netherlands. “That's mainly because of our extensive monitoring and because we have a good early-warning system.” Any poultry farm in the Netherlands that detects an outbreak of an H5 or H7 influenza virus will immediately cull its stock completely. Outbreaks of low pathogenic variants are treated the same way. This killing of healthy animals is often controversial. Recently, the Council on Animal Affairs presented a new advisory report on culling and vaccination policies in outbreaks of animal diseases. Its recommendations included investigating whether poultry farms might be able to avoid total culls in the event of a low pathogenic avian influenza outbreak. It also advises working on vaccines.

Complexities

Even though vaccinating poultry is currently possible, it’s not entirely straightforward. Inactivated vaccines have been developed for the H7 and H5 sub-types, but their use in practice is limited. “The disadvantage of inactivated vaccines is that they aren’t suitable as emergency vaccines in an outbreak, when you need to vaccinate a large number of animals in a short space of time,” says Kortekaas. “When you’re using an inactivated vaccine, each chicken needs to be vaccinated individually, preferably twice. That’s not something you can do quickly.” Extensive administration is also needed in order to guarantee that the vaccination is restricted to the target group, is properly implemented, and has the desired effect.

Furthermore, these vaccines usually only protect against one specific sub-type of the virus. “This is because existing vaccines work by stimulating the antibody response against the virus’s haemagglutinin (HA) protein,” says Kortekaas. “The disadvantage is that viruses are constantly changing and it’s difficult to predict which avian influenza virus will be the next to appear. If the virus in the vaccine isn’t the one that appears in an outbreak, it’s possible that the vaccine won’t be as effective. It would then just reduce the clinical symptoms but not the viral replication in the animals, which would lead to the virus continuing to spread unnoticed in the population and making it more difficult to detect an outbreak.” Furthermore, the availability of a vaccine is not necessarily a solution, because vaccinating takes time and the virus can spread during the one or two weeks it takes animals to develop immunity.

According to Kortekaas, this means emergency vaccinations will not always be effective once the virus is already present in the Netherlands. “It would make more sense to start vaccinating chickens in high-density poultry areas in the Netherlands once we’re aware of any outbreak in another European country.” There’s another important reason why poultry farmers are reluctant to implement vaccination, says Maas. “They’re afraid that they won’t be able to export products that come from their vaccinated animals.” This is because although products from vaccinated animals don’t need to be labelled as such, buyers in European countries including Germany demand a guarantee that products are from unvaccinated animals. They worry that even if they’ve been vaccinated, the imported animals or products could still harbour unidentified viruses. Although the vaccines are available, they are rarely used in the Netherlands and the rest of Europe for the above reasons. This is in spite of the fact that avian influenza poses a serious threat, not just in terms of the economic consequences of an outbreak, but also because of public health risks. Most fatal avian influenza infections in humans are caused by contact with infected birds.

Developing new vaccines

The existing zoonotic risk means there’s increasing pressure to develop effective vaccines. “One important requirement of an avian influenza vaccine is suitability for mass application, for example as a spray or through drinking water,” says Kortekaas. “In principle, that means you need a live vaccine.” Live attenuated avian influenza viruses are not used for vaccinations, due to fears that a co-infection with a wild strain could lead to a more virulent strain through gene exchange. “One way round this problem is to use inactivated influenza vaccines in a powdered form,” says Kortekaas. “Under trial conditions chickens have been vaccinated this way by letting them inhale the powder. But in practice, it’s difficult to achieve the same result in a barn with thousands of chickens.”

Another solution is to develop a live vector vaccine. This uses another type of attenuated virus, made to carry the gene that codes for the influenza virus’s haemagglutinin (HA) protein. When the vector virus infects the bird’s cells, those proteins are produced and they trigger an immune response against the avian influenza virus. “The vector virus itself is unable to spread and is therefore completely safe,” says Kortekaas. One promising vector is a vaccine strain of the Newcastle disease virus (NDV). “Vaccines based on live attenuated NDV already exist, and are suitable for mass application,” says Kortekaas. “If you modify them, you’ll get a vaccine that protects against both Newcastle disease and avian influenza.”

However, the problem is that poultry are currently required to be vaccinated with live attenuated NDV, which means vector vaccines based on NDV will not be effective, as they won’t trigger an immune response against the vector. Another option is to produce synthetic vaccines. These can use certain lipids to hold the genetic code of the HA protein, which means no live virus is used. “The advantage is that these vaccines are very safe and quick to produce and scale up,” says Kortekaas. “On the other hand, they’re also expensive to produce and at present aren’t suitable for mass application.”

Synthetic vaccines do hold potential for human application: work is in progress on synthetic vaccines against the Zika virus and Ebola, for example. But veterinary applications are not imminent. Still, the platform technology (which uses vectors) is still a promising one, according to Kortekaas. “A key advantage is that you can respond very quickly to outbreaks. It’s a sort of plug-and-play approach, where you can easily swap different flu virus haemagglutinin genes so that the vaccine is suited to the virus being passed around at a particular time. It’s also extremely safe.”

Technology striding ahead of regulations

The biggest problem is that regulations are currently miles behind the technological developments. “Technologically, we're at a point where we can make new, effective vaccines very quickly,” says Maas. “But the problem is that the most promising techniques are subject to Europe’s GMO regulations.” That means they have to comply with extra strict rules; for example, each individual member state has to approve their use. Registering a GMO vaccine can often take several years, says Kortekaas. “And that's far too long, because an outbreak can spread all over Europe in just a few months. This means we’re always playing catch-up.”

Another issue is that for each modification, such as inserting a different haemagglutinin gene, the whole process has to happen again. “In the US it’s different,” says Kortekaas. “If they have an outbreak of a new strain, a new vaccine will be ready for application in the field within a few weeks. In Europe it takes months or even more than a year.” Maas agrees. “Regulations need to be changed so that we can respond quickly to new viruses. We need to be able to use the technology, particularly when a virus has zoonotic potential. If we’re going to innovate, regulations need to keep pace with scientific developments.”

This objective is in line with the five-year Zoonotic Anticipation and Preparedness Initiative (ZAPI), which Wageningen Bioveterinary Research is taking part in. The consortium wants to enable swifter responses to new outbreaks, and platform technology can play a part in that. The regulations are already more advanced for human than for veterinary application, according to Kortekaas. “But it’s expected that veterinary regulations will soon include platform technology too. That’s an important development in the context of ‘One Health’ too, because in technological terms veterinary vaccinations are currently the trailblazers. And that knowledge can in turn lead to the development of new human vaccines.”